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In Africa, the scale-up of malaria-control interventions has reduced malaria burden, but progress towards elimination has stalled. Mass drug administration (MDA) is promising as a transmission-reducing strategy, but evidence from low-to-moderate transmission settings is needed. We aimed to assess the safety, coverage, and effect of three cycles of MDA with dihydroartemisinin–piperaquine plus single, low-dose primaquine on Plasmodium falciparum incidence and prevalence in southeast Senegal. We conducted a two-arm, open-label, cluster-randomised controlled trial in villages in the Tambacounda health district of southeast Senegal. Eligible villages had a population size of 200–800, were within a health-post catchment area with an annual malaria incidence of 60–160 cases per 1000 people, and had an established or planned Prise en Charge à Domicile Plus model. We randomly assigned villages (1:1) using a stratified, constrained randomisation approach to receive either three cycles of MDA with oral dihydroartemisinin–piperaquine plus single, low-dose primaquine administered at 6-week intervals (intervention) or to standard of care, which included three cycles of seasonal malaria chemoprevention (SMC) with oral sulfadoxine–pyrimethamine plus amodiaquine administered at 4-week intervals (control). Participants, the field team, and all investigators, including those who assessed outcomes and analysed data, were unmasked to allocation assignment. Laboratory technicians were masked to intervention assignment. The primary outcome was village-level, P falciparum-confirmed malaria incidence in the post-intervention year (ie, July to December, 2022). Secondary outcomes included malaria incidence during the intervention year (ie, July to December, 2021), coverage and safety of MDA, and adverse events. We conducted analyses using an intention-to-treat approach. The trial is registered with ClinicalTrials.gov (NCT04864444) and is completed. Between Sept 1 and Oct 25, 2020, 523 villages were geolocated and screened for eligibility; 111 met the inclusion criteria. Of these, 60 villages were randomly selected and assigned to the intervention arm or control arm. Distribution coverage of all three doses of dihydroartemisinin–piperaquine was 6057 (73·6%) of 8229 participants in the first cycle, 6836 (78·8%) of 8673 participants in the second cycle, and 7065 (81·3%) of 8690 participants in the third cycle. Distribution coverage of single, low-dose primaquine was 6286 (78·6%) of 7999 participants in the first cycle, 6949 (82·1%) of 8462 participants in the second cycle, and 7199 (84·0%) of 8575 participants in the third cycle. Distribution coverage of all three doses of SMC was 3187 (92·2%) of 3457 children aged 3–120 months in the first cycle, 3158 (91·8%) of 3442 children aged 3–120 months in the second cycle, and 3139 (91·4%) of 3434 children aged 3–120 months in the third cycle. In the intervention year (ie, July to December, 2021), the adjusted effect of MDA was 55% (95% CI 28 to 71). In the post-intervention year (ie, July to December 2022), the adjusted MDA effect was 26% (–17 to 53). Malaria incidence during the transmission season of the post-intervention year was 126 cases per 1000 population in the intervention arm and 146 cases per 1000 population in the control arm. No serious adverse events were reported. In southeast Senegal, a low-to-moderate transmission setting where malaria-control measures have been scaled up, three cycles of MDA with dihydroartemisinin–piperaquine plus single, low-dose primaquine was safe and reduced malaria burden during the intervention year. However, its sustained effect was weak and continuation of MDA or another transmission-reducing strategy could be required. US President's Malaria Initiative.

In 2019, the RTS,S/AS01 malaria vaccine (RTS,S) was introduced into Ghana's routine health system as part of the Malaria Vaccine Implementation Programme (MVIP). Household surveys were conducted prior to vaccine introduction and approximately 18 and 30 months post-introduction. We present a description of the area in Ghana based on the baseline household survey including malaria prevalence, malnutrition, wealth, insecticide-treated net (ITN) coverage, other health interventions (deworming, Vitamin A supplementation (VAS)), coverage of Expanded Programme on Immunization (EPI) vaccines, and health-seeking behaviour for febrile children. The baseline household survey was conducted between 25 February and 18 March 2019 in a representative sample of 6778 households across 66 districts (33 in each of the implementing and comparator areas) in Ghana. Caregivers of children aged 5-48 months were interviewed. For each child, vaccination details were transcribed from the maternal and child health record book, and we measured the mid-upper arm circumference and obtained a malaria Rapid Diagnostic Test (RDT). Survey-weighted coverage estimates were obtained using standard survey methods. Survey Poisson regression was used to estimate prevalence ratios. Overall, 7768 children were included in the study, and 21% (95% CI 18-23) tested positive for malaria parasitemia by RDT. About 87%, 95%CI (85-89) of all households owned at least one ITN, and 62%, 95%CI (59-64) of children aged 5-48 months slept under an insecticide-treated net (ITN) the night before the survey. Additionally, 22%, 95%CI (21-24) of children reported having fever in the two weeks preceding the survey; among those with reported fever, 72%, 95%CI (69-74) sought advice or treatment, 40%, 95%CI (37-44) were tested for malaria, and 42%, 95%CI (39-46) of those with fever took an antimalarial drug. Additionally, 17%, 95%CI (16-19) had a mid-upper arm circumference (MUAC) ≤ 13.5 cm, and 1%, 95%CI (0-1) had a (MUAC) ≤ 11.5 cm. The uptake of vitamin A VAS in the 6 months prior to the survey was 36%, based on routine delivery through EPI, and deworming coverage was 29%. Coverage of EPI vaccines was > 90%. Indicators in comparison and implementation areas were comparable. The pilot implementation and evaluation of the RTS,S malaria vaccine in Ghana was conducted in an area with substantial malaria transmission and illness, modest health-seeking behaviour and ITN use, and good EPI vaccine coverage. This study has established the baseline comparability between implementation and comparator areas, which serves as the foundation for future feasibility assessments.

BackgroundThe RTS,S/AS01 malaria vaccine was introduced in Ghana, Kenya, and Malawi in 2019. Evaluation includes case-control studies designed to monitor individual-level safety and effectiveness to complement population-level estimates derived from the MVPE. Here, we discuss design and practical considerations for conducting case-control studies to measure vaccine effectiveness against severe malaria, the need for a 4th dose, and for assessment of safety outcomes. MethodsFor the severe malaria study we aimed to estimate the effectiveness of the primary 3 doses, and of the 4th dose. We also aimed to estimate rebound, if any, in children who received only the primary 3 doses. Cases were patients with severe malaria admitted to a study hospital, residing in an RTS,S/AS01 implementation area, and eligible to have received the 3rd or 4th dose of the vaccine. The case patient’s home is visited to collect data on vaccination status and other details. Four controls are then recruited from the same community, matched closely on date of birth. Vaccination status is determined from home-based records, and from clinic registers. Similar approaches were used for studies of safety outcomes. ResultsWe share preliminary results and discuss the challenges encountered and lessons learned about implementing a multi-centre case control study for a malaria vaccine, and approaches to data collection which have proved effective, including establishing surveillance, the use of specific case definitions standardized across centres, recruiting closely age-matched community controls, and obtaining reliable information from both cases and controls on potential confounding factors which may be associated with both risk of the outcome and with access to vaccination. ConclusionCase control studies are an efficient means of monitoring vaccine effectiveness and safety, but require care in design and implementation. The lessons learned from the malaria vaccine pilots will be useful for countries planning introduction of a malaria vaccine.